Cardiovascular disease is a leading cause of morbidity and mortality in the United States. (Levy et al., N Engl J. Med.; 322:1561-6 (1990); Ho et al., J Am Coll Cardiol.; 22:6A-13A (1993); Dominguez et al., Cardiologia.; 44:801-8 (1999)) Among cardiovascular diseases, cardiomyopathy, disease of the heart muscle, is one of the most common causes of heart failure and of requiring a heart transplant. Cardiomyopathy is generally divided into cardiac hypertrophy (or “hypertrophic cardiomyopathy”; the two terms are used synonymously herein), dilated cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy (ARVC).
Sustained cardiac hypertrophy represents one of the most common causes leading to cardiac failure. (Frey et al., Annu Rev Physiol.; 65:45-79 (2003); Dorn and Molkentin, Circulation.; 109:150-8 (2004)) Once cardiac failure develops, the condition is associated with a very high mortality rate. Cardiac failure therefore represents an important and growing public health problem. Its increasing incidence and prevalence may be in part explained by the progressive aging of the world population. Estimates of prevalence of cardiac failure are 0.4 to 2% of the general population. Half of the patients carrying a diagnosis of heart failure will die within 4 years and patients with severe heart failure will die within 1 year.
In “dilated cardiomyopathy” (also known as “congestive cardiomyopathy”), the volume of the heart enlarges but the muscle becomes weaker. It is the most common form of cardiomyopathy, and often leads to congestive heart failure. Both dilated cardiomyopathy and cardiac hypertrophy are associated with an increased risk of cardiac arrhythmias and sudden cardiac death (“SCD”).
At present, there are few effective pharmacologic therapies cardiac arrhythmias associated with cardiomyopathy and heart failure. Available antiarrhythmic drugs carry a high risk of proarrhythmias and other systemic side effects. (Ruskin, N Engl J Med.; 321:386-8 (1989)) A large number of patients who are deemed to be at high risk for SCD are now given implantable defibrillators, which are both costly and invasive. (Causes of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Am Coll Cardiol.; 34:1552-9 (1999); Moss, Eur Heart J.; 24:16-8 (2003); Moss, J Cardiovasc Electrophysiol.; 14:S96-8 (2003)).
It would be desirable to inhibit or reverse the development of cardiomyopathy and associated arrhythmias. The present invention fills these and other needs.